Despite improvements in public health, advancements in vaccines, and the development of many classes of antibiotics, infectious disease is still responsible for over a quarter of all deaths worldwide. However, even for the most devastating of pandemics, history demonstrates a large variability in the severity and duration of infection. Despite this, few examples of association between human polymorphism and susceptibility to bacteria are known. The goals of this project are to 1) identify aspects of bacterial infection in humans that exhibit heritable variation, 2) determine the genetic changes that are responsible, and 3) assess the relevance of this variation on the fitness of whole organisms. We are measuring intermediate phenotypes of susceptibility using cells derived from populations of apparently normal individuals. Assays of bacterial uptake, replication, and localization, and host-cell survival and cytokine production provide a quantitative, cellular picture of infection. Family-based association analyses are being used to correlate values from these assays with SNPs in candidate genes selected based on relevant cellular microbiology and on a genome-wide scale. Causation of the identified SNPs is being established by a combination of expression analysis, RNA interference, and overexpression experiments. Finally, relevance to health and disease will be measured using association analysis of clinical phenotypes and phenotypic measurements of transgenic mice.